title: Design and evaluation of fragment-like estrogen receptor tetrahydroisoquinoline ligands from a scaffold-detection approach.
abstract: A library of small tetrahydroisoquinoline ligands, previously identified via structure- and chemistry-based hierarchical organization of library scaffolds in tree-like arrangements, has been generated as novel estrogen receptor agonistic fragments via traditional medicinal chemistry exploration. The approach described has allowed for the rapid evaluation of a structure-activity relationship of the ligands concerning estrogen receptor affinity and estrogen receptor β subtype selectivity. The structural biological insights obtained from the fragments aid the understanding of larger analogues and constitute attractive starting points for further optimization.
authors.affiliation: Laboratory of Chemical Biology, Department of Biomedical Engineering, Technische Universiteit Eindhoven, Den Dolech 2, 5612AZ Eindhoven, The Netherlands.
authors.forename: Sabine
authors.initials: S
authors.lastname: Möcklinghoff
authors.forename: Willem A L
authors.initials: WA
authors.lastname: van Otterlo
authors.forename: Rolf
authors.initials: R
authors.lastname: Rose
authors.forename: Sascha
authors.initials: S
authors.lastname: Fuchs
authors.forename: Tobias J
authors.initials: TJ
authors.lastname: Zimmermann
authors.forename: Marta
authors.initials: M
authors.lastname: Dominguez Seoane
authors.forename: Herbert
authors.initials: H
authors.lastname: Waldmann
authors.forename: Christian
authors.initials: C
authors.lastname: Ottmann
authors.forename: Luc
authors.initials: L
authors.lastname: Brunsveld
mesh_terms: D015195:Drug Design; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D047629:Estrogen Receptor beta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D008958:Models, Molecular; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013379:Substrate Specificity; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D008024:Ligands; D054852:Small Molecule Libraries; D044005:Tetrahydroisoquinolines